Resident T cells steer tissue responses in human skin

Abstract: The human skin constitutes a biological barrier against threats to the body from the surrounding environment. Tissue-resident memory cells (TRM) reside in the skin and provide local memory of previous encounters with microbes and pathogens, are poised to promptly eliminating infected cells and elicit tissue-wide defense state. TRM cells are also capable of initiating autoimmunity, aberrant inflammation, and development of skin diseases. The aim of this thesis is to characterize such TRM responses in vitiligo, psoriasis and allergic contact dermatitis (ACD) Paper I: Psoriasis is characterized by the development of well demarked plaques on the skin. However, upon activation of the T cell compartment in never-lesional psoriasis (NLP) areas in patient biopsies led to upregulation of disease-related gene expression. Furthermore, this disease-naïve skin was imprinted with resident T cells subsets capable of producing IFNγ, IL-17 and IL-22 – key cytokines in the pathology observed in psoriasis. This demonstrates that even macroscopically uninvolved skin areas may already be potentiated towards disease development due to the presence of pro-inflammation skewed TRM. Paper II: In allergic contact dermatitis, local eczema appears after re-exposure of the skin to specific allergen. Interrogation of the T cell responses in this disease revealed increased expression of inflammation inducing cytokines, as well as MMP12 which codes for a protein cleaving enzyme. Activation of the resident T cell compartment led to increased production of this enzyme which can degrade the basal membrane separating dermis and epidermis and attract even more lymphocytes in this area. Overall, we observed that in ACD activation of the TRM, leads to tissue remodeling and inflammation exacerbation. Paper III: The hallmark of vitiligo is the appearance of discolored spots with defined boarders in the skin. Spatial transcriptomic analysis of several different areas of patients’ skin revealed that despite lacking depigmentation non-lesional skin showed a broad deregulation of genes. The boarder of the lesion displayed upregulation of responses related to IFNγ – key cytokine in vitiligo’s pathophysiology. T cells from the center of the lesion were also able to elicit such responses after activation. This shows that although appearing less pro-inflammatory at “steady”, non-activated state, these cells still retain pathologic potential. Paper IV: Examining the T cell phenotype and intracellular interaction in limited biopsy material is an experimental challenge. We developed a new method that utilized the NanoStirng GeoMx platform and allows for spatial proteomic analysis of rare cells and cell co-localizations. The method successfully distinguishes between different skin cell types and can elucidate interactions between T cells and melanocytes in vitiligo and healthy skin. Overall, the collected works in this thesis show that TRM cells with pathogenic potential can be found in both lesional, and non-lesional areas in the studied dermatoses. Their activation leads to tissue-wide responses, microenvironmental remodeling, and secretion of pro-inflammatory cytokines.